This application is in response to NIH notice NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications". This competitive revision grant proposes to identify novel peptide inhibitors for the digestive enzyme chymotrypsin C. The parent grant investigates how chymotrypsin C regulates activation and degradation of other digestive enzymes and how mutations in chymotrypsin C increase the risk of chronic pancreatitis in humans. The availability of a highly specific chymotrypsin C inhibitor would facilitate the accomplishment of the specific aims outlined in the parent grant and enhance the overall tempo of the research program. We propose to use phage display technology to select candidate inhibitors;to characterize these inhibitors using both synthetic and natural chymotrypsin C substrates and to determine the structural basis of specific inhibition by co-crystallizing inhibitors with chymotrypsin C. PUBLIC HEALTH RELEVANCE: The present grant proposal intends to develop novel inhibitors against human chymotrypsin C, a digestive enzyme, which plays an important role in regulating other digestive enzymes and has been linked to the development of chronic pancreatitis, an often debilitating disease. The results can advance the development of novel diagnostic and therapeutic interventions for human pancreatitis.